Etravirine, also known as 4-(6-amino-5-bromo-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile, inhibits reverse transcriptase by binding at a non-substrate site on the enzyme, different than that for nucleoside analog reverse transcriptase inhibitors (NRTIs) and nucleotide analog reverse transcriptase inhibitors (NtRTIs). Upon binding to the enzyme at a site proximal to the polymerase active site, etravirine can inhibit the movement of protein domains that are needed to carry out the process of DNA synthesis.
Etravirine is currently approved for human immunodeficiency virus (HIV) infection.
Etravirine in human liver microsomes displays good metabolic stability, degrading by 15% over a 2 hour period (Andries, K et al., Antimicrob Agents Chemother, December 2004, 48(12):4680-6). In humans, etravirine is excreted largely intact, with >85% in the feces and <1% in the urine. Metabolism of etravirine in humans proceeds principally through alkyl oxidation to give the mono- and di-hydroxymethyl derivatives which may then undergo glucuronidation. Oxidative enzymes, CYP3A4 and CYP2C19 are largely responsible for the hydroxylation. (Hendrickx, J et al., AAPS J, 2006, 8(suppl 1): Abst M1342).
In trials with HIV-1-infected patients dosed with etravirine, mild side effects included diarrhea, headache, abdominal pain, acute tonsillitis, flatulence, gastroenteritis, hot flushes, insomnia, intercostal pain, pruritus, somnolence, tachycardia and vomiting (Gruzdev, B et al., Interscience Conference on Antimicrobial Agents and Chemotherapy, 2001, 41st:Chicago, 668). In healthy volunteers administered etravirine in combination with lopinavir/ritonavir, the most common adverse effects of the combined regimen were diarrhea and headache (Piscitelli, S C et al., Interscience Conference on Antimicrobial Agents and Chemotherapy, 2002, 42nd:San Diego, Abs A1824). In phase IIb trials with treatment-experienced patients, the safety and tolerability profile of etravirine was generally comparable with placebo (Lazzarin, A et al., Lancet, Jul. 7, 2007, 370(9581):3-5).
Despite the beneficial activities of etravirine, there is a continuing need for new compounds to treat HIV infection.